Long-term relapse-free survival with supratentorial primitive neuroectodermal tumor in an adult: a case report

Summary Objective In adults, supratentorial primitive neuroectodermal tumor (sPNET) is a very rare undifferentiated embryoblastic neoplasm. Prognosis is worse in comparison to infratentorial medulloblastoma. Older age appears to be prognostically favorable. At present, 5-year survival rates remain below 50% in all age groups. Survival longer than 15 years in an adult has only been reported once so far. Case report In 1987, a 33-year-old-male patient presented with seizures following a six-month’s history of dizziness. CT- and MRI-scans revealed a right occipital tumor with moderate contrast enhancement. The tumor was completely removed. The original histological diagnosis was that of an undifferentiated sarcoma, malignant hemangioendothelioma, grade III. The patient was treated by CyVADIC chemotherapy and conventional radiation therapy (60 Gy). Admission for another reason in 2003 led to a re-evaluation of the original diagnosis. Microscopy revealed a malignant, highly cellular, poorly differentiated tumor with a desmoplastic component. Up to 20% of tumor nuclei were labeled for Ki-67. Almost all cells were stained for neuron specific enolase and NGF-Rp75, with neuronal and glial markers being present to a variable extent. According to these findings, the diagnosis was changed to a sPNET (WHO IV°). Other tumor entities were excluded by immunohistochemistry. Conclusions Although the prognosis of sPNET is reported to be poor, a small fraction with a rather benign biological and clinical behavior exists. Parameters determining long-term-survival in sPNET are not yet known. Whenever possible, complete surgical resection should be attempted followed by postoperative radiotherapy. The value of chemotherapy is an issue of continuous investigation. Supratentorial primitive neuroectodermal tumor is a very rare and highly malignant neoplasm in adults, carrying a poor prognosis. Complete surgical resection followed by radiotherapy proved to be essential for the outcome. We report the case of long-term survival at more than 17 years in an adult patient treated by surgery, postoperative radiation and chemotherapy.     

A clinically relevant orthotopic xenograft model of ependymoma that maintains the genomic signature of the primary tumor and preserves cancer stem cells in vivo

Limited availability of in vitro and in vivo model systems has hampered efforts to understand tumor biology and test novel therapies for ependymoma, the third most common malignant brain tumor that occurs in children. To develop clinically relevant animal models of ependymoma, we directly injected a fresh surgical specimen from a 9-year-old patient into the right cerebrum of RAG2/severe complex immune deficiency (SCID) mice. All five mice receiving the initial transplantation of the patient tumor developed intracerebral xenografts, which have since been serially subtransplanted in vivo in mouse brains for 4 generations and can be cryopreserved for long-term maintenance of tumorigenicity. The xenograft tumors shared nearly identical histopathological features with the original tumors, harbored 8 structural chromosomal abnormalities as detected with spectral karyotyping, maintained gene expression profiles resembling that of the original patient tumor with the preservation of multiple key genetic abnormalities commonly found in human ependymomas, and contained a small population (<2.2%) of CD133⁺ stem cells that can form neurospheres and display multipotent capabilities in vitro. The permanent cell line (BXD-1425EPN), which was derived from a passage II xenograft tumor and has been passaged in vitro more than 70 times, expressed similar differentiation markers of the xenograft tumors, maintained identical chromosomal abnormalities, and formed tumors in the brains of SCID mice. In conclusion, direct injection of primary ependymoma tumor cells played an important role in the generation of a clinically relevant mouse model IC-1425EPN and a novel cell line, BXD-1425EPN. This cell line and model will facilitate the biological studies and preclinical drug screenings for pediatric ependymomas.     

High-dose chemotherapy with autologous stem cell rescue for children with high risk and recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors

Current treatment for high risk and recurrent medulloblastoma (MB) and supratentorial primitive neuroectodermal tumors (stPNET) has a very poor prognosis in children. High dose chemotherapy (HDCT) and autologous stem cell rescue have improved survival rates. We present 19 patients (thirteen classified in the high risk group and six patients with recurrent disease) that received HDCT and autologous stem cell rescue.In the high risk group [Med Pediatr Oncol 38 (2002) 83], all patients underwent neurosurgical debulking. Standard chemotherapy was prescribed in 10 patients. Radiotherapy was given to 4 patients (all older than 4years old). In the recurrence disease group [Childs Nerv Syst 15 (1999) 498], five patients underwent surgery. Radiotherapy was given to those who were not previously irradiated. The HDCT in twelve patients consisted of busulfan 4mg/kg/day, orally over 4days in 6-hourly divided doses and melphalan at a dose of 140mg/m²/day by intravenous infusion over 5min on day –1. Three patients additionally received thiotepa 250mg/m²/day intravenously over 2days and four patients additionally received topotecan 2mg/m²/day over 5days by intravenous infusion over 30min. The other seven patients received busulfan and thiotepa at the same doses.Patients stem cells were mobilized with granulocyte colony-stimulating factor at a dose of 12g/kg twice daily subcutaneously for four consecutive days. Cryopreserved peripheral blood progenitor cells were re-infused 48h after completion of chemotherapy. With a median follow-up of 34months (range 5–93) eight complete responses and one partial response were observed. Three patients died of treatment-related toxicities (15%). The 2 year event-free survival was 37.67±14% in all patients and 57±15% for the high risk group.Therefore we conclude that HDCT may improve survival rates in patients with high risk/recurrent MB and stPNET despite treatment toxicity.     

Congenital peripheral primitive neuroectodermal tumor: A case treated successfully with multimodality treatment

Neonatal tumors comprise less than two percent of childhood malignancies. Most are solid tumors, most common histologies being teratoma and neuroblastoma. We encountered a child who was detected to have a right arm mass on antenatal sonogram, which was diagnosed to be a primitive neuroectodermal tumor involving the triceps on fine needle aspiration cytology performed in the post-natal period. The child was successfully treated with multimodality treatment consisting of surgery, chemotherapy and radiotherapy. We also discuss briefly the problems associated with therapy in neonatal period. A review of all cases reported to have congenital Ewing’s sarcoma family of tumors is presented. Novel therapies are needed to improve efficacy and decrease the devastating side effects of treatment in this age group.     

Cytogenetic and histopathologic studies of congenital supratentorial primitive neuroectodermal tumors: A case report

Primitive neuroectodermal tumors (PNET) represent about 25% of primary central nervous system tumors in childhood, but congenital PNETs are rare. Cytogenetic studies and studies on molecular pathology have identified several genetic alterations in medulloblastoma, but molecular investigations on supratentorial PNETs are infrequent. We present a male newborn with a large congenital PNET of the right cerebral hemisphere and the molecular analysis of the tumor. Tumor tissue was investigated by routine histology and immunohistochemistry. Fluorescence in-situ hybridization was carried out on native tumor tissue to investigate deletions on chromosome 17p and to analyze c-Myc or N-Myc amplifications. Histologic examination revealed a primitive neuroectodermal tumor with massive extension covering almost the entire right hemisphere. Genetic analysis of the native tumor tissue of our patient excluded a deletion of chromosome 17p. An amplification of the c-Myc or N-Myc oncogene was absent using fluorescence in-situ hybridization. Despite unremarkable genetic analysis in our case prognosis was poor, suggesting that there are additional, yet unknown constitutional genetic aberrations in the pathogenesis of congenital supratentorial PNET.     

Growth-inhibiting effect of intratumoral recombinant human tumor necrosis factor on an experimental model of primitive neuroectodermal tumor

The effect of intratumoral administration of recombinant human tumor necrosis factor on an experimental model of primitive neuroectodermal neoplasia was studied. A clear inhibition of tumor growth was achieved by immunotherapy that consisted in intralesion injections of 100 g of tumor necrosis factor daily, the first three days of each week, for a period of four weeks. At this time, tumor size was 2.21 ± 0.66 cm² (mean ±standard deviation) in the treated group, versus 7.62 ± 0.43 cm² in the control group. These data support previous studies on the influence of tumor necrosis factor on the development of ethyl-nitrosourea-induced tumors, and suggest the potential usefulness of this cytokine in human primitive neuroectodermal neoplasms.     

椎管内原始神经外胚层肿瘤1例

原始神经外胚层肿瘤(primitive neuroectodermal tumor,PNET)临床少见,临床及影像学表现无特异性,极易误诊误治,为提高对本病的认识,我科近来收治1例,报道如下并结合文献复习. 1临床资料 患者,女,20岁.于1.5个月前无明显诱因出现双下肢酸软感,以右侧为甚,双下肢活动正常.当时未予注意,未行检查.近1个月来上述症状加重,出现右脚跛行,自觉右下肢无力伴双下肢麻木感,并出现腰背部疼痛,疼痛呈持续性,有针刺感,无放射他处,活动后加重.曾在我院门诊行腰部X线片检查未发现异常.     

A supratentorial primitive neuroectodermal tumor in an adult: a case report and review of the literature

Supratentorial primitive neuroectodermal tumors (sPNET) occurring in adults are rare. Only 56 such cases have been previously reported. This report documents a 56-year-old male who presented with the chief complaint of right facial palsy. Magnetic resonance imaging (MRI) revealed left frontal and bilateral periventricular lesions. Surgery was performed for the frontal mass, which was histologically diagnosed to be sPNET. An immunohistochemistry assay for CD99, and a fluorescence in situ hybridization (FISH) assay for t(11;22) translocation revealed this PNET to be a central PNET. This case was the first case to detect a central PNET using both immunohistochemistry and the FISH assay in adult sPNET. Though radiation therapy was performed, an MRI performed 2.5 months after the surgery revealed a regrowth of the tumor. The patient died 5 months after surgery. This case report is accompanied by a review of 57 cases of adult sPNET.     

A single intravenous injection of oncolytic picornavirus SVV-001 eliminates medulloblastomas in primary tumor-based orthotopic xenograft mouse models

Difficulties of drug delivery across the blood-brain barrier (BBB) and failure to eliminate cancer stem cells (CSCs) are believed to be the major causes of tumor recurrences in children with medulloblastoma (MB). Seneca Valley virus-001 (SVV-001) is a naturally occurring oncolytic picornavirus that can be systemically administered. Here, we report its antitumor activities against MB cells in a panel of 10 primary tumor-based orthotopic xenograft mouse models. We found that SVV-001 killed the primary cultured xenograft cells, infected and replicated in tumor cells expressing CSC surface marker CD133, and eliminated tumor cells capable of forming neurospheres in vitro in 5 of the 10 xenograft models. We confirmed that SVV-001 could pass through BBB in vivo. A single i.v. injection of SVV-001 in 2 anaplastic MB models led to widespread infection of the preformed intracerebellar (ICb) xenografts, resulting in significant increase in survival (2.2-5.9-fold) in both models and complete elimination of ICb xenografts in 8 of the 10 long-term survivors. Mechanistically, we showed that the intracellular replication of SVV-001 is mediated through a subverted autophagy that is different from the bona fide autophagic process induced by rapamycin. Our data suggest that SVV-001 is well suited for MB treatment. This work expands the current views in the oncolytic therapy field regarding the utility of oncolytic viruses in simultaneous targeting of stem and nonstem tumor cells.     

Differentiation of a primitive neuroectodermal tumor into a benign ganglioglioma

We describe a case of cerebellar neuroblastoma with histologic documentation of maturation into a ganglioglioma sixteen months later. Only chemotherapy was administered following the initial surgery and the child is well and disease-free three years following her final surgical procedure. The outcome of this patient supports previous hypotheses that the cerebellar neuroblastoma may be a less malignant tumor than its other primitive neuroectodermal posterior fossa counterparts. Furthermore, this case suggests a role for second-look surgery in the management of selected pediatric brain tumors.     

Isolated cardiac peripheral primitive neuroectodermal tumor: A case report

Background: Peripheral primitive neuroectodermal tumor isolated in the heart, presenting as a primary cardiac tumor is considered as extremely rare.

Methods: We present a 53-year-old Chinese female with a cardiac tumor which was discovered by CT.

Results: A hypo-intense tumorous mass was shown extending from the left ventricle by Cardiac CT, and fused FDG positron emission tomography demonstrated no other abnormal FDG active lesions in the body. We performed a total resection surgery of the tumor subsequently and the patient recovered well and discharged from hospital 6 d after surgery.

Conclusion: The pathological diagnosis was primary cardiac peripheral primitive neuroectodermal tumor. No tumor recurrence was shown by echocardiography during the 24 months follow-up visits.     

儿童原始神经外胚叶肿瘤的临床特征(附4例临床报告及文献复习)

目的 探讨儿童大脑神经外胚叶肿瘤的临床特点及治疗方法。方法 对我院1999年1月至2003年1月收治的4例小儿大脑神经外胚叶肿瘤的临床资料进行回顾性分析。结果 4例病人1例位于额叶，2例位于顶叶，1例位于颞叶。OT显示为高或等密度影，MRI为短TI长T2信号，增强后均匀强化，肿瘤有明显界线。4例均在显微镜下全切，病理诊断：原始神经外胚叶肿瘤。术后均行放疗。术后8个月～18个月复发。结论 小儿大脑原始神经外胚叶肿瘤为高度恶性的肿瘤，预后差手术加放疗能延长生存时间。     

Cerebral primitive neuroectodermal tumor in an adult,with spinal cord metastasis after 18-year dormancy

A cerebral primitive neuroectodermal tumor in a 40-year-old man recurred as a metastasis to the spinal cord after an 18-year dormant period. The metastatic tumor showed features of neuronal differentiation. The clinical course and pathologic findings are discussed.     

Cytogenetic confirmation of a gastrointestinal stromal tumor and ewing sarcoma/primitive neuroectodermal tumor in a single patient

We report a rare case in which two tumor entities, a gastrointestinal stromal tumor (GIST) and Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET), with distinct cytogenetic features occurred in a single patient. The patient was a 72-year-old woman. The first tumor was a submucosal gastric tumor and was diagnosed as a low-risk group GIST based on morphological characteristics and the results of an immunohistochemical analysis for c-kit and CD34. Further cytogenetic analysis revealed that this tumor had a point mutation (D842V substitution) in exon 18 of the platelet-derived growth factor receptor alpha gene. The second tumor was found more than 4 years after the appearance of the first tumor. ES/PNET was highly suspected both morphologically and immunohistochemically, and the diagnosis was confirmed by the detection of an EWS rearrangement using a fluorescence in situ hybridization technique. Although the cytogenetic correlations of these two tumors are unclear, accurate histologic recognition is of clinical importance because the treatments for these two tumors differ.     

肾脏原始神经外胚叶肿瘤一例报告并文献复习

原始神经外胚叶肿瘤(primitive neuroectodermal tumor,PNET)发源于神经嵴胚胎残留组织,具有多向分化潜能,且临床上较原始的恶性小圆细胞肿瘤少见,多分布于颅内、四肢、胸壁及中轴软组织[1-2]。Celli等[3]1975年首次报道PNET,大部分发病于儿童和青年人,>70%的患者发病于20岁之前,女性多见。     

Ewing sarcoma/primitive neuroectodermal tumor of the ureter:A case report and literature review

Ewing sarcoma/primary neuroectodermal tumors are rare,invasive,and small round blue cell tumors.There are few reports of its occurrence in the urinary system.Here,we present the first middle-aged female patient whose Ewing sarcoma primary site was in the ureter.The main clinical manifestation was intermittent hematuria.She was in good health after complete surgical resection and adjuvant radiotherapy.To date,there has been no recurrence or metastasis.Accurate early diagnosis and appropriate treatment can help prolong survival.18F-fluorodeoxyglucose positron emission tomography/computed tomography is expected to be an effective means of evaluating treatment effects and detecting metastasis and recurrence.In this article,besides introducing a case of Ewing sarcoma/primitive neuroectodermal tumor of the ureter,we review the literature to discuss the current status of diagnosis and treatment.     

Plumbagin,a medicinal plant (Plumbago zeylanica)-derived 1,4-naphthoquinone,inhibits growth and metastasis of human prostate cancer PC-3M-luciferase cells in an orthotopic xenograft mouse model

We present here first time that Plumbagin (PL), a medicinal plant-derived 1,4-naphthoquinone, inhibits the growth and metastasis of human prostate cancer (PCa) cells in an orthotopic xenograft mouse model. In this study, human PCa PC-3M-luciferase cells (2 × 10⁶) were injected into the prostate of athymic nude mice. Three days post cell implantation, mice were treated with PL (2 mg/kg body wt. i.p. five days in a week) for 8 weeks. Growth and metastasis of PC-3M-luciferase cells was examined weekly by bioluminescence imaging of live mice. PL-treatment significantly (p = 0.0008) inhibited the growth of orthotopic xenograft tumors. Results demonstrated a significant inhibition of metastasis into liver (p = 0.037), but inhibition of metastasis into the lungs (p = 0.60) and lymph nodes (p = 0.27) was not observed to be significant. These results were further confirmed by histopathology of these organs. Results of histopathology demonstrated a significant inhibition of metastasis into lymph nodes (p = 0.034) and lungs (p = 0.028), and a trend to significance in liver (p = 0.075). None of the mice in the PL-treatment group showed PCa metastasis into the liver, but these mice had small metastasis foci into the lymph nodes and lungs. However, control mice had large metastatic foci into the lymph nodes, lungs, and liver. PL-caused inhibition of the growth and metastasis of PC-3M cells accompanies inhibition of the expression of: 1) PKCε, pStat3Tyr705, and pStat3Ser727, 2) Stat3 downstream target genes (survivin and Bcl_xL), 3) proliferative markers Ki-67 and PCNA, 4) metastatic marker MMP9, MMP2, and uPA, and 5) angiogenesis markers CD31 and VEGF. Taken together, these results suggest that PL inhibits tumor growth and metastasis of human PCa PC3-M-luciferase cells, which could be used as a therapeutic agent for the prevention and treatment of human PCa.     

Antitumor effect of novel anti‐podoplanin antibody NZ‐12 against malignant pleural mesothelioma in an orthotopic xenograft model

Podoplanin (aggrus) is highly expressed in several types of cancers, including malignant pleural mesothelioma (MPM). Previously, we developed a rat anti‐human podoplanin mAb, NZ‐1, and a rat–human chimeric anti‐human podoplanin antibody, NZ‐8, derived from NZ‐1, which induced antibody‐dependent cellular cytotoxicity (ADCC) and complement‐dependent cytotoxicity against podoplanin‐positive MPM cell lines. In this study, we showed the antitumor effect of NZ‐1, NZ‐8, and NZ‐12, a novel rat–human chimeric anti‐human podoplanin antibody derived from NZ‐1, in an MPM orthotopic xenograft SCID mouse model. Treatment with NZ‐1 and rat NK (CD161a⁺) cells inhibited the growth of tumors and the production of pleural effusion in NCI‐H290/PDPN or NCI‐H226 orthotopic xenograft mouse models. NZ‐8 and human natural killer (NK) (CD56⁺) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Furthermore, NZ‐12 induced potent ADCC mediated by human MNC, compared with either NZ‐1 or NZ‐8. Antitumor effects were observed following treatment with NZ‐12 and human NK (CD56⁺) cells in MPM orthotopic xenograft mice. In addition, combined immunotherapy using the ADCC activity of NZ‐12 mediated by human NK (CD56⁺) cells with pemetrexed, led to enhanced antitumor effects in MPM orthotopic xenograft mice. These results strongly suggest that combination therapy with podoplanin‐targeting immunotherapy using both NZ‐12 and pemetrexed might provide an efficacious therapeutic strategy for the treatment of MPM.     

The establishment of a new mouse model with orthotopic esophageal cancer showing the esophageal stricture

We established a promising new experimental animal model with an orthotopic xenograft of esophageal cancer that successfully represents poor oral intake, a major clinical feature of esophageal cancer. The advantage of this model is that no surgical technique is required, only the injection of a cell suspension by a needle and syringe via the esophageal lumen from the mouth, which provides a high reproducibility of tumor implantation and a rapid progress of outcome. We propose that this model is useful to study cancer-related outcomes and for developing new therapies for esophageal cancer, and we expect it to make a contribution to clinical practice.